Structural analogs of S-adenosylhomocysteine (SAH) are being synthesized and evaluated as inhibitors of S-adenosylmethionine-dependent methyl-transferases in an effort to detect differences in the structural requirements needed to bind to the active sites of these enzymes. Studies are also being carried out to design, synthesize, and biologically evaluate inhibitors of S-adenosylhomocysteinase. Inhibition of this enzyme in vivo would elevate intracellular levels of SAH and thereby produce overall inhibition of methylases. The inhibitory activity of these compounds on nucleic acid methylation systems, including both rat liver t-RNA methylases and viral and cellular mRNA methylases, are being studied. These compounds are also being tested as inhibitors of protein carboxymethylation and phospholipid methylation in rat hypothalamic synaptosomes. In addition, the effects of SAH analogs on several small molecule methylases, including catechol-O-methyltransferase, histamine-N-methyltransferase, hydroxyindole-O-methyltransferase, and indolethylamine-N-methyltrasferase are being determined. By evaluation of the SAH analogs prepared in our studies as inhibitors of these methyltransferase systems, it is hoped that differences in inhibitory specificity will be detected which can be used to design enzyme specific inhibitors.